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A 60-year-old woman presents to her gynecologist complaining of recent onset of vaginal bleeding. An endometrial biopsy showed adenocarcinoma. A hysterectomy and bilateral salpingoopherectomy was submitted for examination. The gross examination of the uterine corpus showed a 2.0 cm thick endometrium with apparent luminal necrosis.

Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2009, case 6, and is high grade endometrioid uterine carcinoma, Grade 3 (G3EC).

Criteria for Diagnosis and Comments:
On low power examination, the section of the uterine wall contains an extensively necrotic luminal tumor with deep myometrial invasion and readily identifiable tumor emboli within lymphovascular spaces. The tumor is a solid growth of infiltrating poorly differentiated carcinoma with focal areas of adenocarcinoma with associated squamous differentiation. The adenocarcinoma is a cribriform growth composed of tubular glands. The glands are lined by pseudostratified columnar cells with elliptical nuclei containing numerous nucleoli. The architectural and nuclear features are compatible with FIGO system grade 3 endometrioid carcinoma (G3EC).

Endometrial carcinoma is the most common malignancy of the uterine corpus. The peak age of incidence is 55 – 65 years of age. Based on demographic and histopathologic studies, two general subsets (type 1 or type 2) of endometrial carcinoma have been recognized. The type 1 endometrial carcinoma is the common subset, associated with some form of chronic unopposed estrogen stimulation, is usually sporadic, low stage and predominately low grade endometrioid type of endometrial carcinoma. Other risks for type 1 endometrial carcinoma include tamoxifen therapy and occasionally familial syndromes such as hereditary non-polyposis colorectal carcinoma syndrome (HNPCC; Lynch syndrome) and Cowden’s syndrome. The endometrioid tumors associated with HNPCC are more likely to be poorly differentiated as compared to sporadic cases. Endometrioid carcinoma has been associated with PTEN tumor suppressor gene mutation and microsatellite instability. The type1 tumors infrequently exhibit p53 mutations. In contrast, type 2 endometrial carcinoma subset is the minority of endometrial carcinomas. Type 2 tumors are high grade histological subtypes of endometrial carcinoma, uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC) and overall type 2 tumors have a poor prognosis. These histological subtypes are frequently associated with p53 mutation and are frequently seen in patients with HNPCC. Tamoxifen related tumors however are infrequently type 2 tumors.

The vast majority of uterine corpus tumors (80 – 85%) are estrogen dependent low grade neoplasms predominantly of the endometrioid type of endometrial carcinoma. Endometrioid uterine carcinoma is defined as a carcinoma composed of confluent glands resembling those of normal proliferative endometrium. These carcinomas are frequently associated with endometrial hyperplasia. The presence of pseudostratified columnar cells forming tubular glands is characteristic of the endometrioid type. A number of metaplasias (squamous, syncytial, ciliated cell, oxyphilic, spindled, etc) may be seen with endometrioid carcinoma. Squamous metaplasia is seen in approximately 25% of endometrioid tumors. The vast majority of endometrioid carcinomas are grade 1 or 2 in contrast to this current case. The prognostic value of grading endometrioid tumors has been established. Within the widely adopted FIGO system, as malignant solid nests and sheets of tumor predominate, the tumor increases in grade. The architectural grade of the tumor is scaled on the amount of malignant solid areas (less than 5% grade1, 5 – 50% solid-grade2, greater than 50% solid grade 3) and modified by the presence or absence of bizarre nuclear atypia (grade 3: marked nuclear pleomorphism, coarse chromatin, prominent nucleoli). The presence of marked nuclear atypia will increase the overall grade of the neoplasm by one unit (grade 1 to grade 2, grade 2 to grade 3). Tumors possessing extensive bizarre nuclear atypia suggest the carcinoma may in fact represent UPSC or CC. On histologic subtype alone UPSC and CC are classified as high risk endometrial carcinomas.

High risk endometrial carcinoma occurs in the minority of patients with carcinoma of the uterine corpus but accounts for the majority of uterine cancer deaths. High risk carcinomas, endometrioid (G3EC) and non-endometrioid (UPSC, CC) types are associated with deep myometrial invasion, lymphovascular invasion, lymph node metastasis and a correspondingly lower survival rate. There is conflicting data in current literature regarding the prognosis of these three high risk endometrial tumors. In large studies with multivariate analysis G3EC seems to be a favorable histology as compared to UPSC and CC. The five year disease-specific survivals for UPSC, CC and G3EC, were reported as 55, 68 and 78%, respectively. Survival differences between these high risk cancers persist requiring the segregation of G3EC from UPSC and CC. The vast majority of these tumors can be distinguished on morphology and molecular markers. Serous carcinoma, in contrast to endometrioid carcinoma, will exhibit cleft-like spaces lined or filled with exfoliated cells with high grade nuclei having a high nuclear to cytoplasmic ratio. In addition to differing morphology, UPSC readily shows p53 immunoreactivity. CC grows in a sheet with tubulocystic or tubular pattern which lacks pseudostratification of the lining cells. The cells have a polygonal outline, clear cytoplasm, high grade nuclei and PAS-positive acellular matrix. CC demonstrates immunoreactivity for p53 although intermediate between endometrioid carcinoma and UPSC.